ADAM17-deficiency on microglia but not on macrophages promotes phagocytosis and functional recovery after spinal cord injury

  • Brain Behav Immun. 2019 Aug;80:129-145. doi: 10.1016/j.bbi.2019.02.032.
Daniela Sommer  1 ,  Inge Corstjens  1 ,  Selien Sanchez  1 ,  Dearbhaile Dooley  2 ,  Stefanie Lemmens  1 ,  Jana Van Broeckhoven  1 ,  Jeroen Bogie  1 ,  Tim Vanmierlo  3 ,  Pia M Vidal  4 ,  Stefan Rose-John  5 ,  Myriam Gou-Fabregas  1 ,  Sven Hendrix  6
Affiliations
  • 1. Biomedical Research Institute, Hasselt University, 3500 Hasselt, Belgium.
  • 2. Health Science Centre, School of Medicine, University College Dublin, Dublin 4, Ireland.
  • 3. Biomedical Research Institute, Hasselt University, 3500 Hasselt, Belgium; Division of Translational Neuroscience, MHeNs, Maastricht University, 6229ER Maastricht, the Netherlands.
  • 4. Laboratory of Neuroimmunology, Fundación Ciencia & Vida, 7780272 Santiago, Chile.
  • 5. Institute of Biochemistry, Christian-Albrechts University Kiel, 24098 Kiel, Germany.
  • 6. Biomedical Research Institute, Hasselt University, 3500 Hasselt, Belgium. Electronic address: [email protected].
PMID: 30851378 DOI: 10.1016/j.bbi.2019.02.032
Abstract

A disintegrin and metalloproteinase 17 (ADAM17) is the major sheddase involved in the cleavage of a plethora of cytokines, Cytokine Receptors and growth factors, thereby playing a substantial role in inflammatory and regenerative processes after central nervous system trauma. By making use of a hypomorphic ADAM17 knockin mouse model as well as pharmacological ADAM10/ADAM17 inhibitors, we showed that ADAM17-deficiency or inhibition significantly increases clearance of apoptotic cells, promotes axon growth and improves functional recovery after spinal cord injury (SCI) in mice. Microglia-specific ADAM17-knockout (ADAM17flox+/+-Cx3Cr1 Cre+/-) mice also showed improved functional recovery similar to hypomorphic ADAM17 mice. In contrast, endothelial-specific (ADAM17flox+/+-Cdh5Pacs Cre+/-) and macrophage-specific (ADAM17flox+/+-LysM Cre+/-) ADAM17-knockout mice or bone marrow chimera with transplanted ADAM17-deficient macrophages, displayed no functional improvement compared to wild type mice. These data indicate that ADAM17 expression on microglia cells (and not on macrophages or endothelial cells) plays a detrimental role in inflammation and functional recovery after SCI.

Keywords
ADAM17; Inflammation; Macrophages; Microglia; Spinal cord injury.
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